Clinical research into the biology and treatment of acute leukemia is pursued with particular emphasis on acute lymphoblastic leukemia (ALL) of childhood. Major issues being addressed include: 1) development of therapeutic strategies aimed at improving overall prognosis of children with ALL, 2) investigation into the mechanisms of treatment failure with particular emphasis on evaluation of pharmacologic approaches to leukemic therapy, 3) characterization of adverse sequelae of antileukemic therapy and design of treatment regimens which avoid them, and 4) studies of the biology of ALL aimed at improving our basic understanding of the biology of this disease, identifying new diagnostic and prognostic tests and providing insight into the biologic basis for treatment failure. An earlier ALL treatment protocol demonstrated that high-dose, protracted systemic methotrexate infusions could substitute for cranial radiation as central nervous system (CNS) preventive therapy for the majority of patients with ALL. Analysis of data from this study also identified a patient group at particular risk for CNS relapse. A subsequent, high risk protocol was devised to improve the prognosis for these and other poor risk patients. The results of that study indicated that the therapy was highly effective in preventing both systemic and central nervous system relapses while avoiding the use of cranial radiation. A new protocol for high risk patients is attempting to demonstrate that dose intensification, accomplished through the concomitant use of G-CSF, will improve the prognosis for this patient group. In this study molecular analysis (pcr) will be performed to evaluate minimal residual disease. A major, multi-institutional pharmacologic monitoring protocol which has studied the relationship between the bioavailability of orally administered maintenance chemotherapy and relapse in children with ALL has recently been completed and the results are being analyzed. Study of the clinical pharmacology of the thiopurines, mercaptopurine and thioguanine, has led to the development of new therapeutic approaches with these agents. Several new intrathecal chemotherapy approaches have been developed to provide new therapy for patients with central nervous system leukemia. Collaborative studies are evaluating the role of the P53 gene, a candidate tumor suppressor gene, in the pathogenesis of this disease.